Blood removal therapy in hereditary hemochromatosis induces a stress response resulting in improved genome integrity.

Abstract

Hereditary hemochromatosis (HH) is a common disease of iron metabolism, manifesting with iron overload and affecting up to 1% of individuals of northern European descent. Untreated HH can result in irreversible damage of the liver and pancreas, potentially leading to cancer and diabetes. Therapy consists of normalizing iron stores by repeated blood donations (phlebotomy). Treated HH patients have normal survival rates and report less tiredness after phlebotomy; however, it is not understood why musculoskeletal symptoms may persist in spite of iron removal. We hypothesize that phlebotomy therapy does not simply reverse iron accumulation but has additional effects at the subcellular level. In particular, the systemic impact of phlebotomy on mitochondria and genome integrity is largely unknown. The effects of phlebotomy therapy on mitochondrial iron proteins and genome integrity were investigated in peripheral blood mononuclear blood cells from HH patients. After the reduction of systemic iron load in these patients with phlebotomy, we observed increased expression of mitochondrial superoxide dismutase, reduced iron sulfur assembly protein (Iscu1/2), and improved genome integrity. We conclude that phlebotomy therapy in HH does not merely restore systemic iron homeostasis, but induces an "oxidative stress" defense response that manifests as improved genome integrity. These findings provide novel insights into an ancient therapy.